Exposure to multiple high doses of methamphetamine (METH) produces damage to the dopamine (DA) innervation of striatum. Several events post-synaptic to DA terminals and occurring during or within ~8 hrs after administration of a neurotoxic regimen of METH (Stage I) are implicated in the neurotoxicity. However, the nature of the relation between these post-synaptic events and the neurotoxic consequences of that treatment on the DA nerve terminal is less clear. A novel approach by which to determine the interplay between these factors is to examine effects of neurotoxic regimens of METH on these parameters in populations resistant to the neurotoxicity. Preliminary data show that rats with partial DA loss induced by high doses of METH do not exhibit further striatal DA loss when later re-exposed to a neurotoxic regimen of METH. Consequently, it appears that animals with partial striatal DA depletion are resistant to further METH-induced neurotoxicity. Furthermore, data from our laboratory suggest that partial DA loss induced by METH is associated with long-term alterations in DA D1-family receptor regulation of striatal neurons. Interestingly, in addition to striatonigral efferent neurons, the interneurons in striatum that express neuronal nitric oxide synthase (nNOS) express only DA D1-family (D1 and D5) receptors. Phasic dopamine neurotransmission acting on DA D1-family receptors regulates these striatal neuron populations. Therefore, the overall hypothesis of this project is that alterations in DA D1 receptor-mediated regulation of striatonigral and nNOS-containing interneurons during Stage I in rats pretreated with a neurotoxic regimen of METH render these animals resistant to METH-induced expression of other Stage 1 and 2 events and long-term DA terminal toxicity. The following aims will test this hypothesis. 1) Examine the effects of prior METH-induced striatal DA loss on the expression and activity of nitric oxide synthase, the generation of reactive nitrogen species and glial activation by subsequent exposure to a neurotoxic dosing regimen of METH. 2) Examine the effects of prior METH-induced striatal DA loss on systems-level changes in basal ganglia circuitry contributing to METH-induced neurotoxicity. 3) Determine whether inhibiting activation of nNOS-containing interneurons and striatonigral efferent neurons in the striatum blocks the development of Stage 1 and Stage 2 processes and DA terminal loss by a neurotoxic regimen of METH. 4) Examine the effects of DA D1-family receptor manipulations on METH-induced neurotoxicity in normal PD90 rats and in rats with prior depletion of striatal dopamine. These studies will provide novel insight into the role of DA D1-family receptor activation, nNOS-containing striatal interneurons, and striatonigral efferent neurons in METH-induced Stage 1 and 2 events and ultimate neurotoxicity to striatal DA nerve terminals. These findings will be compared to results from Projects 1 and 3 to determine similarities and differences, with the ultimate intent to design targeted interventions to address the neurotoxic potential of METH.